Substituted glycineamides



ilnited States Patent 3,055,937 SUBSTITUTED GLYCENEAMIDES Andre L.Langis, St. Laurent, Quebec, and Hilda M. McConltey, Montreal, Quebec,Canada, assignors to American Home Products Corporation, New York, N.Y., a corporation of Delaware No Drawing. Filed Oct. 6, 1960, Ser. No.60,775 7 Claims. (Cl. 260559) This invention relates to new chemicalcompounds which are useful for producing dilation of the peripheralblood vessels. Our invention is also concerned with a process by whichthese compounds may be prepared.

Our new chemical compounds, possessing pharmacological activity asdilators of the peripheral blood vessels, may be chemically regarded asderivatives of glycinamide. They may be generically characterized by thefollowing formula where R is a methoxy. The methoxy group may be presentin ortho, meta or para position.

In preparing our novel compounds we prefer to start with a methoxyphenylbenzylamino butanol of the formula on on3 @d-dnnnnom-Q R (|)H where R,as above, is a methoxy group in ortho, meta or para position. Thiscompound is reacted with N- a-chloracetyl-fl-phenethylamine to producethe desired novel compound.

Details of the procedures carried out in the reaction are given in thefollowing illustrative examples. Generally we prefer to bring themethoxyphenyl benzylamino butanol and N-a-chloracetyl-fi-phenethylaminetogether at the temperature of reflux and in the presence of an acidacceptor such as sodium carbonate.

The starting material, 3-benzylamino-2-methoxyphenyl- Z-butanol, whereinthe methoxy group may be in ortho, meta or para position, may beprepared in accordance with the process described in US. Patent No.2,854,483.

-a-chloracetyl-fi-phenethylamine may be prepared in various ways, as byreacting chloracetyl chloride with phenethylamine following theprocedure which is disclosed, for example, in U.S. Patent No. 2,768,166.

Our procedure for the preparation of the novel compounds may beindicated as follows:

CH: C 3

CH CH3 OH H2 In this diagrammatic representation of the reaction, R

represents a methoxy group which may be in ortho, meta or para positionon the benzene ring.

Included as pharmacologically active compounds which possess activity indilating the peripheral blood vessels, in accordance with our invention,are the compounds:

Acid addition salts of these compounds, such as the hydrochloride salts,have the advantage of being crystalline and are readily prepared. Theypossess the same pharmacological activity as the bases.

EXAMPLE 1 N-3 (o-Methoxyphenyl-Z-Butanol-Z )N-Benzyl- ,B-PhenethylGlycinamia'e 5.0 grams (0.015 mole) ofo-methoxyphenyl-Z-benzylamino-3-butanol-2 and 3.0 grams (0.015 mole) ofN-a-chloracetyl-fi-phenethylamine in 25 milliliters of butanol wererefluxed in the presence of 1.58 grams (0.015 mole) of sodium carbonatefor 12 hours. Water was added to dissolve the remaining precipitate andthe oil layer separated, washed and dried. Crystallization from etheryielded 2.0 grams of pure material melting at 137-138 C. The product wasN-3(o-methoxypheny1- 2-butanol-2)N-benzyl-li-phenethyl glycinamide.

Analysis confirmed the empiric formula C H O N Ten grams of the abovebase were converted to the hydrochloride salt by addition of a solutionof hydrogen chloride in ether, and the resulting salt was crystallizedfrom hot isopropanol, yielding 8.3 grams of crystalline material meltingat 206-207" C.

Analysis confirmed the empiric formula C H O N Cl for the hydrochloridesalt.

EXAMPLE 2 N-3 (m-Methoxyphenyl-Z-Butan0l-2)N-Benzyl S-PhenethylGlycinamide 10.7 grams (0.034 mole) ofm-methoxyphenyl-Z-benzylamino-3-butanol-2 and 6.7 grams (0.034 mole) ofN-m-chloracetyl-fi-phenethylamine in 50 milliliters of butanol wererefluxed in the presence of 3.6 grams (0.034 mole) of sodium carbonatefor 24 hours. The process then proceeded in the manner described inExample 1, by the addition of water to the reaction mixture, followed byremoval, washing and drying of the oil layer which separated. Theresulting product, N- 3(m-methoxyphenyl-2-butanol-2)Nbenzyl-fi-phenethyl glycinamide, did not crystallize despite repeatedattempts and was recovered in the form of an oil.

This base, N-3 (m-methoxyphenyl 2-butanol-2)N-benzyl-B-phenethylglycinamide, was then converted to the hydrochloride salt by theaddition of a solution of hydrogen chloride in ether. This hydrochloridesalt was then crystallized from mixed isopropanol-ether. The resultingcrystalline material, in the amount of 5.0 grams, melted at C., withdecomposition.

Analysis confirmed the empiric formula C H O N Cl for the hydrochloridesalt.

EXAMPLE 3 N-3 (p-Methoxyphenyl-Z-Butanol-2)N-Benzylfi-PhenethylGlycinamia'e 3 4 sodium carbonate for 12 hours. The process was car- 2.A compound of the formula ried out in the manner described in Example 1to yield CH3 CH3 2.0 grams of pure material melting at 118ll9 C. Theproduct was N-3(p-methoxyphenyl-2 butanol-2)N-ben- JJflH NOH"OO'NHCHLCHT zyl-fl-phenethyl glycinamide. 5 R 0 a Analysis confirmedthe empiric formula C H O N The hydrochloride salt of N-3(p-methoxyphenyl-Z- butanol-Z)N-benzyl-fi-phenethyl glycinamide results,as before, by treatment of the base with a solution of hydrogen chloridein ether, followed by recrystallization 10 from a suitable solvent suchas isopropanol. Where R r pre e ts a methoxy group.

We claim: 3. N-3(o-methoxyphenyl Z-butanol 2)N -benzyl-B- l. A compoundselected from the group which conphenfithyl glycinamidesists of asubstituted glycinamide of the formula YP Y 2 -D Y -fl' CH3 CH3 15phenethyl glycinamide. 5 A} 5. N-3(p-methoxyphenyl Z-butanol 2)N-benzyl-B- HNOH2.CO.NH.CHz.CH@ phenethyl glycinamide. R 1m $111, 6. Thehydrochloride salt of N-3(m-methoxyphenyl2-butanol-2)N-benzyl-B-phenethyl glycinamide. 0 7. The hydrochloride saltof N-3(o-methoxyphenyl-2- butanol-2 N-benzyl-fl-phenethyl glycinamide.

References Cited in the file of this patent where R represents a methoxygroup, and the hydro- UNITED STATES NT chloride Salts thereofi 2,700,680Bruce et al Jan. 25, 1955

1. A COMPOUND SELECTED FROM THE GROUP WHICH CONSISTS OF A SUBSTITUTEDGLYCINAMIDE OF THE FORMULA